5,6-dihydro-napth[1,2-d]-imidazole, napth[1,2-d]imidazole, and chromane[3,4-d]imidazole derivatives

ABSTRACT

Disclosed are 5,6-Dihydro-napth[1,2-d]-imidazoles, Naphth[1,2-d]imidazoles, and Chromane[3,4-d]imidazoles compounds having the formula:                    
     and the pharmaceutically acceptable salts thereof, wherein, 
     A represents ethenylene, or A represents —X—CH 2 —; where X is CH 2  or oxygen, provided that when X is oxygen, the oxygen is adjacent the 6-membered ring; 
     R 1 , R 2 , R 3  and R 4  are inorganic or organic substituents; and 
     R 5  and R 6  is are optionally substituted organic substituents; or 
     NR 5 R 6  represents a carbocyclic or heterocyclic six membered ring optionally substituted with various organic or inorganic groups. Such compounds are useful in the treatment of neuropsychological disorders.

This application is a continuation of 09/371,066, filed Aug. 9, 1999,now U.S. Pat. No. 6,211,366, which is a continuation of 08/913,116,filed Jan. 20, 1998, now U.S. Pat. No. 5,948,912, which is a nationalphase of PCT/US96/01906, filed Feb. 14, 1996, which is acontinuation-in-part of 08/463,759, filed Jun. 5, 1995, now U.S. Pat.No. 5,773,616, which is a continuation-in-part of 08/461,310, filed Jun.5, 1995, now abandoned, which is a continuation-in-part of 08/461,143,filed Jun. 5, 1995, now abandoned, which is a continuation of08/389,111, filed Feb. 15, 1995, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain bridged4-phenyl-2-aminomethylimidazoles which selectively bind to dopaminereceptor subtypes. This invention also relates to pharmaceuticalcompositions comprising such compounds. It further relates to the use ofsuch compounds in the treatment of affective disorders such asschizophrenia, depression as well as certain movement disorders such asParkinsonism and dystonia. Furthermore compounds of this invention areuseful in treating the extrapyramidal side effects associated with theuse of conventional neuroleptic agents.

2. Description of the Related Art

Schizophrenia or psychosis is a term used to describe a group ofillnesses of unknown origin which affect approximately 2.5 millionpeople in the United States. These disorders of the brain arecharacterized by a variety of symptoms which are classified as positivesymptoms (disordered thought, hallucinations and delusions) and negativesymptoms (social withdrawal and unresponsiveness). These disorders havean age of onset in adolescence or early adulthood and persist for manyyears. The disorders tend to become more severe during the patient'slifetime and can result in prolonged institutionalization. Within theUnited States of America, approximately 40% of all hospitalizedpsychiatric patients suffer from schizophrenia.

During the 1950's physicians demonstrated that they could successfullytreat psychotic (schizophrenic) patients with medications calledneuroleptics. This classification of antipsychotic medication was basedlargely on the activating (neuroleptic) properties of the nervous systemby these drugs. Subsequently, neuroleptic agents were shown to increasethe concentrations of dopamine metabolites in the brain. This findingsuggested that altered neuronal firing of the dopamine systemcontributed in some way to the aberrant behavior observed inschizophrenic patients. Additional evidence indicated that dopaminecould increase the activity of adenylate cyclase in the corpus striatum,an effect reversed by neuroleptic agents. Thus, cumulative evidence fromthese and later experiments strongly suggested that the neurotransmitterdopamine was involved in schizophrenia.

One of the major actions of antipsychotic medication is the blockade ofdopamine receptors in brain. Several dopamine systems appear to exist inthe brain and at least five classes of dopamine receptors appear tomediate the actions of this transmitter. These dopamine receptors differin their pharmacological specificity and were originally classified onthe basis of their ability to bind various dopaminergic ligands.

The butyrophenones are a class of drugs containing many potentantipsychotic drugs. Perhaps the most prominent member of this class ofcompounds is the antipsychotic drug haloperidol(1-(3-p-fluorobenzoylpropyl)-4-p-chlorophenyl-4-hydroxypiperidine).Haloperidol binds relatively weakly at the major dopamine receptorsubtype which activates adenylate cyclase (commonly classified as the D₁dopamine receptor). In contrast, haloperidol displayed binding affinityat a dopamine receptor subtype which suppressed the activity ofadenylate cyclase (commonly classified as D₂ receptors) in thesubnanomolar range.

Recently, three additional dopamine receptor subtypes have beenidentified using the often congruent sciences of receptor pharmacologyand molecular biology. These new dopamine receptors have been labeled asD₃, D₄, and D₅. The D₃ and D₄ subtypes are pharmacologically related tothe D₂ receptor via their ability to suppress the activity of adenylatecyclase. Conversely, the D₅ receptor is classified as a “D₁-like”dopamine subtype through its ability to stimulate cyclase activity.

Recently, a new group of drugs (such as sulpiride and clozapine) havebeen developed with a lesser incidence of extrapyramidal side effects(EPS) than classical neuroleptics. In addition, there is some indicationthat they may be more beneficial in treating negative symptoms in somepatients. Since all D₂ blockers do not possess a similar profile,hypotheses underlying the differences have been investigated. Majordifferences have been detected in the anticholinergic actions of thesedrugs. It has also been suggested that the dopamine receptors in motorareas may differ from those in the limbic areas which are thought tomediate the antipsychotic responses. The existence of the D₃, D₄ and D₅and other as yet undiscovered dopamine receptors may contribute to thisprofile. Some of the atypical compounds possess similar activity at D₂,D₃ and D₄ receptors. The examples of this patent fall into this generalclass of molecules.

Using molecular biological techniques it has been possible to clonecDNAs coding for each of the pharmacologically defined receptors. Thereare at least two forms of D₁ which have been identified as D₁ and D₅,and two forms of D₂, identified now as D₂ and D₄ dopamine receptors. Inaddition, there is at least one form of D₃ dopamine receptor.

International Publication No. WO 94/22839 describes certain2-aminomethylbenzimidazoles as having affinity at dopamine receptors.The compounds of the present invention differ from those in WO 94/22839in that the compounds of this invention possess a aromatic benzene ringfused in a [4,5-e] fashion to the benzimidazole substructure.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact withdopamine receptor subtypes.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in treatingaffective disorders such as schizophrenia and depression as well ascertain movement disorders such as Parkinsonism. Furthermore, compoundsof this invention are useful in treating the extrapyramidal side effectsassociated with the use of conventional neuroleptic agents. Sinceparticularly dopamine D₃ and D₄ receptor subtypes are concentrated inthe limbic system (Science, 265: 1034 (Taubes, 1994)) which controlscognition and emotion, compounds which interact with these receptors areuseful in the treatment of cognitive disorders. Such disorders includecognitive deficits which are a significant component of the negativesymptoms (social withdrawal and unresponsiveness) of schizophrenia.Other disorders involving memory impairment or attention deficitdisorders can also be treated with the compounds of this invention thatinteract specifically with dopamine D₃ and/or D₄ receptor subtypes.Accordingly, a broad embodiment of the invention is directed tocompounds of Formula I:

wherein

A represents —CH═CH—, or A represents ═X—CH₂—, where X is CH₂ or oxygen,provided that when X is oxygen, the oxygen is adjacent the 6-memberedring;

R₁, R₂, R₃ and R₄ are the same or different and represent hydrogen,halogen, hydroxy, amino, aminosulfonyl, alkylaminosulfonyl,alkylsulfonyl, arylalkylsulfonyl, alkyl of 1 to 6 carbon atoms or alkoxyof 1 to 6 carbon atoms; and

R₅ represents alkyl having 1-3 carbon atoms and R₆ is benzyl, optionallysubstituted with alkyl having 1-6 carbon atoms, alkoxy, hydroxy, orhalogen; or

NR₅R₆ represents heterocyclic six membered ring optionally substitutedwith alkyl having 1-6 carbon atoms, hydroxyl, halogen, aryl, alkylarylwhere the alkyl portion is alkyl having 1-6 carbon atoms, or heteroaryl.

The invention also pertains to the use of compounds of general Formula Iin the treatment of neuropsychological disorders. The pharmaceuticalutility of compounds of this invention is indicated by the assaysdescribed below for dopamine receptor subtype affinity.

DETAILED DESCRIPTION OF THE INVENTION

In addition to compounds of general formula I described above, thepresent invention further encompasses compounds of Formula II:

or the pharmaceutically acceptable salts thereof wherein:

A represents —CH═CH—, or A represents ═X—CH₂—; where X is CH₂ or oxygen,provided that when X is oxygen, the oxygen is adjacent the 6-memberedring;

Y represents nitrogen or CH;

W, Y and Z are the same or different and represent either carbon ornitrogen,

R₁, R₂, R₃, R₄, R₅, R₆, and R₇ independently represent hydrogen,halogen, hydroxy, amino, aminosulfonyl, arylalkylsulfonyl oralkylsulfonyl where each alkyl portion has 1 to 6 carbon atoms,alkylaminosulfonyl where the alkyl portion has 1 to 6 carbon atoms,alkyl having 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms;

R₁₀ and R₁₁ are the same or different and represent alkyl groups having1 to 6 carbon atoms;

g is an integer from 0 to 4; and

W and Z are both nitrogen; or

W is CR₈ and Z is CR₉; or

W is CR₈ and Z is nitrogen; or

Z is CR₉ and W is nitrogen,

where R₈ and R₉ are the same or different and represent hydrogen,halogen, alkyl having from 1 to 6 carbon atoms, or alkoxy having from 1to 6 carbon atoms.

The invention also encompasses compounds of formula III:

or the pharmaceutically acceptable salts thereof wherein:

X is CH₂ or oxygen,

Y represents nitrogen or CH;

W, Y and Z are the same or different and represent either carbon ornitrogen,

R₁, R₂, R₃, R₄, R₅, R₆, and R₇ independently represent hydrogen,halogen, hydroxy, amino, aminosulfonyl, arylalkylsulfonyl oralkylsulfonyl where the alkyl portion has 1 to 6 carbon atoms,alkylaminosulfonyl where each alkyl portion has 1 to 6 carbon atoms,alkyl having 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms;

R₁₀ and R₁₁ are the same or different and represent alkyl groups having1 to 6 carbon atoms;

g is an integer from 0 to 4; and

W and Z are both nitrogen; or

W is CR₈ and Z is CR₉; or

W is CR₈ and Z is nitrogen; or

Z is CR₉ and W is nitrogen,

where R₈ and R₉ are the same or different and represent hydrogen,halogen, alkyl having from 1 to 6 carbon atoms, or alkoxy having from 1to 6 carbon atoms.

The invention further encompasses compounds of formula IV:

or the pharmaceutically acceptable salts thereof wherein

Y represents nitrogen or CH;

W, Y and Z are the same or different and represent either carbon ornitrogen,

R₁, R₂, R₃, R₄, R₅, R₆, and R₇ independently represent hydrogen,halogen, hydroxy, amino, aminosulfonyl, arylalkylsulfonyl oralkylsulfonyl where each alkyl portion has 1 to 6 carbon atoms,alkylaminosulfonyl where the alkyl portion has 1 to 6 carbon atoms,alkyl having 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbon atoms;

R₁₀ and R₁₁ are the same or different and represent alkyl groups having1 to 6 carbon atoms;

g is an integer from 0 to 4; and

W and Z are both nitrogen; or

W is CR₈ and Z is CR₉; or

W is CR₈ and Z is nitrogen; or

Z is CR₉ and W is nitrogen,

where R₈ and R₉ are the same or different and represent hydrogen,halogen, alkyl having from 1 to 6 carbon atoms, or alkoxy having from 1to 6 carbon atoms.

The invention also provides compounds of formula V:

wherein,

X is CH₂ or oxygen,

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are the same or different andrepresent hydrogen, halogen, hydroxy, amino, aminosulfonyl,arylalkylsulfonyl, alkylsulfonyl, alkylaminosulfonyl, alkyl of 1 to 6carbon atoms or alkoxy of 1 to 6 carbon atoms.

The invention also provides compounds of formula VI:

wherein,

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀ and R₁₁ are the same ordifferent and represent hydrogen, halogen, hydroxy, amino,aminosulfonyl, arylalkylsulfonyl, alkylsulfonyl, alkylaminosulfonyl,alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms.

The invention also provides compounds of formula VII:

wherein

X is CH₂ or oxygen,

R₁, R₂, R₃, R₄ and R₅ are the same or different and represent hydrogen,halogen, hydroxy, amino, aminosulfonyl, arylalkylsulfonyl,alkylsulfonyl, alkylaminosulfonyl, alkyl of 1 to 6 carbon atoms oralkoxy of one to six carbon atoms.

The invention also provides compounds of formula VIII:

wherein

X is CH₂ or oxygen,

R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are the same or different and representhydrogen, halogen, hydroxy, amino, aminosulfonyl, arylalkylsulfonyl,alkylsulfonyl, alkylaminosulfonyl, alkyl of 1 to 6 carbon atoms oralkoxy of 1 to 6 carbon atoms.

The invention also provides compounds of formula IX:

wherein

X is CH₂ or oxygen,

R₁, R₂, R₃, and R₄ are the same or different and represent hydrogen,halogen, hydroxy, amino, aminosulfonyl, arylalkylsulfonyl,alkylsulfonyl, alkylaminosulfonyl, alkyl of 1 to 6 carbon atoms oralkoxy of 1 to 6 carbon atoms.

The invention also provides compounds of formula X:

wherein

R₁, R₂, R₃, R₄, R₅, and R₆ are the same or different and representhydrogen, halogen, hydroxy, amino, aminosulfonyl, arylalkylsulfonyl,alkylsulfonyl, alkylaminosulfonyl, alkyl of 1 to 6 carbon atoms oralkoxy of 1 to 6 carbon atoms.

The invention further provides compounds of the formula:

or the pharmaceutically acceptable salts thereof wherein:

Y represents nitrogen or CH;

R₁, R₂, R₃, and R₄ are the same or different and represent hydrogen oralkyl groups having 1 to 6 carbon atoms;

R₅, R₆, and R₇ independently represent hydrogen, halogen, hydroxy,amino, alkyl having 1 to 6 carbon atoms, or alkoxy of 1 to 6 carbonatoms; and

W and Z are the same or different and represent nitrogen or CR₉ where R₉represents hydrogen, halogen, alkyl having from 1 to 6 carbon atoms, oralkoxy having from 1 to 6 carbon atoms.

In addition, the invention provides compounds of the formula:

or the pharmaceutically acceptable salts thereof wherein:

X represents oxygen or methylene;

R₁, R₂, R₃, and R₄ are the same or different and represent hydrogen oralkyl groups having 1 to 6 carbon atoms; and

R₅ represents alkyl having 1-3 carbon atoms and R₆ is benzyl, optionallysubstituted with alkyl having 1-6 carbon atoms, alkoxy, hydroxy, orhalogen.

The invention also provides compounds of the formula:

or the pharmaceutically acceptable salts thereof wherein:

Y represents nitrogen or CH;

R₁, R₂, R₃, and R₄ are the same or different and represent hydrogen oralkyl groups having 1 to 6 carbon atoms;

R₆ represents hydrogen, halogen, hydroxy, amino, alkyl having 1 to 6carbon atoms, or alkoxy of 1 to 6 carbon atoms; and

W and Z are the same or different and represent nitrogen or CR₉ where R₉represents hydrogen, halogen, alkyl having from 1 to 6 carbon atoms, oralkoxy having from 1 to 6 carbon atoms.

Preferred “NR₅R₆” groups of formula I above include the following:

In the above preferred NR₅R₆ groups, OR represents hydroxy or alkoxy.

Particularly preferred NR₅R₆ substituents are N-benzyl-N-methyl,4-(2-pyrimidinyl)piperazinyl, and 4-phenylpiperidinyl groups.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in FIG. Iand their pharmaceutically acceptable salts. Non-toxic pharmaceuticallyacceptable salts include salts of acids such as hydrochloric,phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluene sulfonic,hydroiodic, acetic and the like. Those skilled in the art will recognizea wide variety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which can be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

When A represents —CH═CH— in the formulas set forth above, the resultingunsaturated system is a 1H-naphth[1,2-d]imidazole.

By “aryl” and “Ar” is meant an aromatic carbocyclic group having asingle ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), whichcan optionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By “alkyl” and “lower alkyl” is meant straight and branched chain alkylgroups having from 1-6 carbon atoms.

By “lower alkoxy” and “alkoxy” is meant straight and branched chainalkoxy groups having from 1-6 carbon atoms.

By “heteroaryl” is meant 5, 6, or 7 membered aromatic ring systemshaving at least one hetero atom selected from the group consisting ofnitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridyl,pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl,furanyl, quinolinyl, isoquinolinyl, thiazolyl, and thienyl, which canoptionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By halogen is meant fluorine, chlorine, bromine and iodine.

By alkylsulfonyl is meant a sulfonyl group substituted with a loweralkyl group.

By arylalkylsulfonyl is meant a sulfonyl group substituted with anarylalkyl group.

By aminosulfonyl is meant a sulfonyl group substituted with an aminogroup.

By alkylaminosulfonyl is meant a sulfonyl group substituted with a loweralkylamino, or di-lower alkylamino group.

Representative examples of bridged 4-phenyl-2-aminomethylimidazolesaccording to the invention are shown in Table 1 below.

TABLE 1¹

¹The number below each compound is its compound number.

The pharmaceutical utility of compounds of this invention are indicatedby the following assays for dopamine receptor subtype affinity whichdemonstrate the Interaction of the compounds with dopamine receptorsubtypes. The interaction results in the pharmacological activities ofthese compounds which thus can be exploited in the treatment ofaffective disorders such as schizophrenia, depression as well as certainmovement disorders such as Parkinsonism and dystonia. Furthermore,compounds of this invention are useful in treating the extrapyramidalside effects associated with the use of conventional neuroleptic agents.

Assay for D₂ and D₃ receptor binding activity

Pellets of COS cells containing recombinantly produced D2 or D3receptors from African Green monkey were used for the assays. The sampleis homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 4° C.and pH 7.4. The sample is then centrifuged at 30,000×g and resuspendedand rehomogenized. The sample is then centrifuged as described and thefinal tissue sample is frozen until use. The tissue is resuspended 1:20(wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl.

Incubations are carried out at 48° C. and contain 0.4 ml of tissuesample, 0.5 nM ³H-YM 09151-2 and the compound of interest in a totalincubation of 1.0 ml. Nonspecific binding is defined as that bindingfound in the presence of 1 μM spiperone; without further additions,nonspecific binding is less than 20% of total binding. The bindingcharacteristics of examples of this invention for the D₂ and D₃ receptorsubtypes are shown in Table 2.

TABLE 2 Compound Number¹ D₂ K_(i) (μM) D3 K_(i) (μM) 1 4.200 7.800 20.350 0.210 3 0.220 0.440 ¹Compound numbers relate to compounds shown inTable 1.

Assay for D₄ receptor binding activity

Clonal cell lines expressing the human dopamine D₄ receptor subtype wereharvested in PBS and the cells centrifuged and the pellets stored at−80° C. until used in the binding assay. The pellets were resuspendedand the cells lysed at 4° C. in 50 mM Tris pH 7.4 buffer containing 120mM NaCl, 1 mM EDTA and 5 mM MgCl₂. The homogenate is centrifuged at48000×g for 10 minutes at 4° C. The resulting pellet is resuspended infresh buffer and centrifuged again. After resuspension of the pellet infresh buffer a 100 ml aliquot is removed for protein determination. Theremaining homogenate is centrifuged as above, the supernatant removedand the pellet stored at 4° C. until needed at which time it isresuspended to a final concentration of 625 mg/ml (250 mg per sample)with 50 mM Tris buffer (pH 7.4) and 120 mM NaCl just prior to use.Incubations were carried out for 60 minutes at 25° C. in the presence of0.1 nM [³H] YM-09151-2. The incubation was terminated by rapidfiltration through Whatman GF/C filters and rinsed with 2×4 ml washes ofchilled 50 mM Tris (pH 7.4) and 120 mM NaCl. Non-specific binding wasdetermined with 1 μM spiperone and radioactivity determined by countingin an LKB beta counter. Binding parameters were determined by non-linearleast squares regression analysis, from which the inhibition constantK_(i) could be calculated for each test compound. The bindingcharacteristics of some examples of this invention are shown in Table 3for the dopamine D₄ binding assay. In general, compounds of theaccompanying Examples were tested in the above assay, and all were foundto possess a K_(i) value for the displacement of [³H]YM-09151-2 from thehuman dopamine D₄ receptor subtype of below 500 nM. Some specific datais indicated in Table 3.

TABLE 3 Compound Number¹ K_(i) (μM) 1 0.012 2 0.081 3 0.145 ¹Compoundnumbers relate to compounds shown in Table 1.

Compounds 1 and 2 are particularly preferred embodiments of the presentinvention because of its potency in binding to dopamine receptorsubtypes.

The compounds of the invention, or a pharmaceutically acceptable satthereof, i.e., the “active ingredient”, can be used alone or incombination with various excipients, stabilizers or agents to designedto prolong the action of the active ingredient in the treatment ofneuropsychochological disorders such as, example, schizophrenia,dementia, depression, anxiety, Parkinson-like motor disorders and motiondisorders related to the use of neuroleptic agents.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water.Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Representative procedures suitable for the preparation of compounds ofthe present invention are illustrated in Schemes 1 and 2. Those havingskill in the art will recognize that the starting materials may bevaried and additional steps employed to produce compounds encompassed bythe present invention.

Scheme 1 depicts a representative route for the preparation of ethyl andoxomethyl bridged 4-phenyl-2-aminomethylimidazoles of the invention.

Scheme 2 shows a representative route for the preparation of theethylene bridged 4-phenyl-2-aminomethylimidazoles of the invention.

In each of Schemes 1 and 2 above, NRR′ represents the group NR₅R₆defined above or a protected precursor thereof.

This invention is further illustrated by the following examples whichare not to be construed as limiting the invention in scope or spirit tothe specific procedures and compounds described therein.

EXAMPLE 1

1. A solution of bromine (5.5 g) in 25 ml of acetic acid was addeddropwise to a solution of 1-tetralone in 25 ml of acetic acid at 60° C.After the addition was complete, the reaction was cooled and most of theacetic acid was removed in vacuo. The residue was partitioned betweenwater and ethyl acetate. The organic layer was washed with a dilutesolution of sodium bisulfite, dried with sodium sulfate andconcentrated. A portion of the resulting 2-bromo-1-tetralone (3 g) wasmixed with 30 ml of formamide and the resulting solution was heated at160° C. for 12 hours. Upon cooling, 100 ml of water was added followedby 10 ml of 3N hydrochloric acid solution. The mixture was washed withdiethyl ether and the ether layer was discarded. The remaining solutionwas made basic with saturated sodium carbonate solution and extractedwith methylene chloride. The organic extracts were dried with sodiumsulfate and concentrated to provide 1.2 g of4,5-dihydronaphth[1,2-d]imidazole.

2. A solution of 100 mg of 4,5-dihydronaphth[1,2-d]imidazole, 51 mg of37% w/w aqueous formaldehyde, 103 mg of 1-(2-pyrimidinyl)piperazine in 5ml of acetic acid was refluxed for 1 hour, cooled and the solventremoved under reduced pressure. Ethanol (3 ml) and ammonium hydroxide(0.1 ml) were added and the solution was reconcentrated. Purification ofthe product on silica gel using 10% v/v methanol/chloroform as theeluent provided1H-2-(1-(4-(2-pyrimidyl)piperazinyl)methyl-(5,6-dihydro)-naphth[1,2-d]-imidazoleas an oil. The addition of a saturated solution of hydrogen chloride inisopropanol to the product in isopropanol yielded the amine salt whichwas isolated by filtration to provide 151 mg of:1H-2-(1-(4-(2-pyrimidyl)piperazinyl))methyl-(5,6-dihydro)-naphth[1,2-d]imidazoledihydrochloride (Compound 1, m.p. 212-214° C.).

EXAMPLE 2

The following compounds are prepared essentially according to theprocedure described in Example 1.

(a)1H-{2-(N-benzyl-N-methyl)aminomethyl}-(5,6-dihydro)-naphth[1,2-d]imidazoledihydrochloride (Compounds 2, m.p. 225-227° C.).

(b) 1H-{2-(N-benzyl-N-methyl)aminomethyl}chromano[3,4-d]imidazoledihydrochloride (Compound 3, m.p. 198-201° C. dec.).

EXAMPLE 3

Monochloroacetic acid (15 g, 0.16 mol) and diaminonaphthlene (22.1 g,0.14 mol) were refluxed in 60 ml of 5 N HCl for 6 hours. The reactionwas cooled in ice and neutralized with aqueous ammonium hydroxide. Theprecipitated product was collected by filtration and recrystallized frombenzene/hexane (18.7 g, 62%).

To a solution of the isolated 2-chloromethyl-1H-naphth[1,2-d]imidazole(1.4 g, 6.5 mmol) in dimethylformamide (20 ml) was added potassiumcarbonate (2 g) and the resultant mixture was refluxed for 2 hours.After cooling to 20° C. the reaction mixture was poured onto ice waterand extracted with chloroform. The organic extracts were dried andconcentrated to give an oil. The oil was dissolved in 10 ml of isopropylalcohol and 48% HBr was added dropwise until the pH of the solution wasless than 3.0 as indicated by pH paper. A precipitate developed uponstanding which was isolated by filtration providing1H-2-(1[4-(2-methoxyphenyl)-piperazinyl)]methylnaphth[1,2-d]imidazoledihydrobromide (Compound 4, 2.7 g, 77%).

EXAMPLE 4

The following compounds are prepared essentially according to theprocedure described in Example 3.

(a) 2-[1-(4-phenyl)piperidinyl]methyl-1H-naphth[1,2-d]imidazoledihydrochloride (Compound 5).

(b)2-[1-{4-phenyl-1,2,3,6-tetrahydro}pyridyl]methyl-1H-naphth[1,2-d]imidazoledihydrochloride (Compound 6).

(c)2-[1-{4-hydroxy-4-(4-chlorophenyl)}piperidinyl]methyl-1H-naphth[1,2-d]imidazoledihydrochloride (Compound 7).

The invention and the manner and process of making and using it are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude the specification.

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt thereof wherein, X is CH₂ oroxygen; and R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₉ are the same ordifferent and represent hydrogen, halogen, hydroxy, amino,aminosulfonyl, arylalkylsulfonyl, alkylsulfonyl, alkylaminosulfonyl,alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms.
 2. Acompound of the formula:

or a pharmaceutically acceptable salt thereof wherein, R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, and R₁₁ are the same or different and representhydrogen, halogen, hydroxy, amino, aminosulfonyl, arylalkylsulfonyl,alkylsulfonyl, alkylaminosulfonyl, alkyl of 1 to 6 carbon atoms oralkoxy of 1 to 6 carbon atoms.
 3. A compound of the formula

or a pharmaceutically acceptable salt thereof wherein X is CH₂ oroxygen; and R₁, R₂, R₃, R₄, and R₅ are the same or different andrepresent hydrogen, halogen, hydroxy, amino, aminosulfonyl,arylalkylsulfonyl, alkylsulfonyl, alkylaminosulfonyl, alkyl of 1 to 6carbon atoms, or alkoxy of one to six carbon atoms.
 4. A compound of theformula:

or a pharmaceutically acceptable salt thereof wherein X is carbon oroxygen; and R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are the same or different andrepresent hydrogen, halogen, hydroxy, amino, aminosulfonyl,arylalkylsulfonyl, alkylsulfonyl, alkylaminosulfonyl, alkyl of 1 to 6carbon atoms or alkoxy of 1 to 6 carbon atoms.
 5. A compound of theformula

or a pharmaceutically acceptable salt thereof wherein: X is CH₂ oroxygen; and R₁, R₂, R₃, and R₄ are the same or different and representhydrogen, halogen, hydroxy, amino, aminosulfonyl, arylalkylsulfonyl,alkylsulfonyl, alkylaminosulfonyl, alkyl of 1 to 6 carbon atoms, oralkoxy of 1 to 6 carbon atoms.
 6. A compound of the formula

or a pharmaceutically acceptable salt thereof wherein X is CH₂ oroxygen; and R₁, R₂, R₃, R₄, R₅, and R₆ are the same or different andrepresent hydrogen, halogen, hydroxy, amino, aminosulfonyl,arylalkylsulfonyl, alkylsulfonyl, alkylaminosulfonyl, alkyl of 1 to 6carbon atoms, or alkoxy of 1 to 6 carbon atoms.